DME is a form of angioedema that is caused by the leaking of blood vessels which lead to fluid accumulating in the macula, a region at the back of the eye that is responsible for central vision. DME eventually causes blindness.
KVD001 is a small molecule that blocks the activity of plasma kallikrein, an enzyme that increases blood vessel leakiness and edema (swelling). To prevent the accumulation of fluids at the back of the eye associated with DME, the treatment must be administered by an intravitreal (inside the eye) injection.
The safety and efficacy of KVD001 at preventing vision loss in DME patients was investigated in a randomized Phase 2 trial (NCT03466099) that was sponsored by KalVista.
The study enrolled 129 DME patients who failed to respond to standard-of-care treatment with anti-angiogenic therapies (medications that limit blood supply to an area of the body).
“This trial studied a challenging DME patient population with significant persistent vision loss despite prior therapies,” Lloyd Paul Aiello, MD, PhD, professor of ophthalmology at Harvard Medical School, said in a press release.
Once enrolled, participants were randomly assigned to receive four intravitreal injections of KVD001 (at a dose of 3μg or 6μg), or a sham control treatment, over three months. All participants were followed for an additional three months after completing the treatment.
The study’s primary efficacy endpoint was to assess changes in the best corrected visual acuity from baseline until week 16 (four months). Secondary endpoints included assessing the central subfield thickness (macula thickness) and disease severity using the diabetic retinopathy severity scale.
Study findings showed that those who received intravitreal injections of KVD001 at the highest dose were able to read 2.6 additional letters compared to those who received the sham treatment. Those treated with the lowest dose of the medication were able to read 1.5 additional letters compared to controls.
In both cases, the differences were not sufficient to be considered statically significant, meaning that the trial failed to meet its primary efficacy endpoint. Likewise, no statistically significant differences were found in any of the secondary endpoints.
“Although the study did not meet the primary endpoint, KVD001 demonstrated what we believe is an important dose responsive clinical benefit on vision in the overall population,” Andrew Crockett, CEO of KalVista, said.
Despite not leading to statistically significant improvements in visual acuity, KVD001 was found to protect patients from losing their vision. Analyses showed that more than half of those receiving the sham treatment (54.5%) lost part of their vision, while a lower percentage (32.5%) had the same experience in the group receiving the highest dose of KVD001.
In addition, a pre-specified subgroup analysis that investigated the influence of visual acuity at baseline on patients’ response to treatment, revealed that those with less severe vision loss at the study’s start experienced higher improvements in visual acuity after receiving the highest dose of KVD001 (4.9 additional letters compared to sham).
“We identified a substantial proportion of patients who experienced a more robust response to treatment, that we believe warrants further study,” Crockett said. “These data and the safety profile also support continued evaluation of oral plasma kallikrein inhibitors as a treatment for DME.”
Safety assessments showed that KVD001 was generally safe and well-tolerated by patients. No serious drug-related serious adverse events were reported during the study.
“This was the first study to evaluate the efficacy of a plasma kallikrein inhibitor in DME,” Crockett said. “There is a significant population of DME patients who do not respond sufficiently to anti-VEGF therapies, and we want to express our gratitude to these patients as well as the healthcare providers and others who participated.”
Aiello added: “These study data support the possibility that plasma kallikrein inhibition prevents worsening vision in patients with DME and that KVD001 warrants additional study in this regard as a method to treat this disease.”